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Sapir Karli, Amit K Patel, Krishna R Surapaneni, BaoXang Li, Hyun Yi, Abigail S Hackam; Regulation of Photoreceptor Survival and Tissue Remodeling by the Wnt Pathway. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1719.
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© ARVO (1962-2015); The Authors (2016-present)
A major obstacle for treating retinal degenerations is pathologic tissue remodeling, which leads to aberrant neurite growth and gliosis. We tested the hypothesis that activating Wnt signaling specifically in Muller glia will increase photoreceptor survival and decrease neuronal remodeling in the rd10 mouse model of retinal degeneration. We also evaluated whether Wnt regulates remodeling independently of photoreceptor protection.
Mice were subretinally injected with adenovirus containing non-secreted Wnt activator β-cateninS33A or Wnt inhibitor β-eng genes, both under control of the 2.2kb GFAP promoter. GFP and PBS were injection controls. Photoreceptor survival was measured by nuclei row counts, ERG’s and Western blotting. Tissue remodeling was assessed by co-localization of the GFP reporter in the adenovirus with GFAP or Ki67, and by Western blotting for PKCα.
GFP labeling indicated that the genes were delivered to at least a third of the retina, and its expression co-localized with Muller glia markers. β-cateninS33A increased Wnt signaling by 2.5-fold, compared with control injections (n=3). Muller glia-specific Wnt activation increased the number of photoreceptor rows by 44% compared with Wnt inhibition (n=5, p<0.01), increased a-wave amplitudes by 4.5-fold, and increased rhodopsin and cone transducin levels by 2-5-fold (n=3). Furthermore, Wnt activation reduced PKCα levels by 2-fold in both wildtype mice and rescued rd10 mice, indicating reduced neuronal remodeling. In contrast, Wnt increased PKCα by 1.8-fold in post-degeneration retinas showing increased remodeling in absence of protection. There was also a significant reduction in GFAP-positive activated Muller glia in retinas injected with the Wnt activator compared with the Wnt inhibitor (n=3, p<0.01), and no change in the number of proliferating Ki67-positive Muller glia.
We demonstrated that Wnt plays a neuroprotective role by increasing photoreceptor survival while concomitantly decreasing neuronal remodeling during degeneration. In contrast, Wnt signaling increases remodeling post degeneration, indicating that its role in remodeling is independent of its protective functions. These results will allow us to determine an appropriate Wnt activation treatment window for retinal degeneration, during which there is neuroprotection without tissue reorganization to keep the retina functionally viable.
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